OA is a chronic disease featured with bone and joint degeneration. Imposing serious hazards to human health, OA currently lacks effective treatment. Therefore, a need exists for new methods of effectively preventing and/or treating OA. Clinical and pathological features of arthritis include cartilage damage resulting from proteolysis of the extracellular matrix (ECM). Cartilage ECM degradation caused by increased proteolytic activity acts as a direct cause for cartilage degeneration, ultimately leading to cartilage damage. Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) have significant functional involvement in hFLS cell catabolism and ECM degradation. Studies have shown the presence of IL-1 and TNF-α at high concentrations in arthritis patients' synovial fluid. These proteins are considered key pro-inflammatory cytokines, playing an important role in the pathogenesis of arthritis.
A Disintegrin And Metalloproteinase with Thrombospondin Motifs (ADAMTS) is a family of secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in embryonic development, angiogenesis, coagulation, and inflammation. With 19 members, the family uses a variety of ECM components as substrates. The ADAMTS family shares a high degree of protein structural similarity. For example, the members contain a proprotein domain following an N-terminal signal peptide sequence and undergo a post-translational cleavage to become active proteases. In addition, the proteases include at the C-terminal at least one conservative TSPI-like repeat motif, which mediates binding of the proteases with the ECM.
ADAMTS-5 catalyzes aggrecan degradation as a type of aggrecanases or proteoglycanases. Two major cleavage sites exist in aggrecan: a matrix metalloproteinase (MMP) cleavage site located at Asn341 and Phe342, and an aggrecanase cleavage site located at Glu373 and Ala374. Abundant aggrecan present in the articular cartilage helps to improve the tension and anti-pressure force at the joints. Severe aggrecan damage has been discovered in OA and RA patients. Thus, aggrecanases have become a new target for treating arthritis and other diseases. For example, in malignant glioma, the expression level of ADAMTS-5 significantly increases, leading to glioma invasion and metastasis as a result of aggrecan degradation. In addition, extracellular protein degradation or damage may cause diseases such as cancer, asthma, chronic obstructive pulmonary disease, atherosclerosis, age-related macular degeneration, myocardial infarction, hepatitis, tendonitis, angiogenesis, multiple sclerosis, glomerulonephritis, osteopenia, and periodontal diseases.
ADAM17 belongs to the A Disintegrin And Metalloprotease (ADAM) family. As a class of cell surface glycoproteins, the ADAM family plays a role in a variety of physiological and pathological processes, such as cell-cell and cell-matrix adhesion, cell fusion, ECM degradation, signal transduction, and tumor formation, growth, and metastasis. ADAM17 is also known as TNF-α converting enzyme (TACE), which produces free TNF-α by releasing membrane-bound TNF-α. Free TNF-α in turn causes excessive secretion of inflammatory cytokines, cell apoptosis, and intracellular signaling disorders, leading to a variety of diseases, including RA, systemic Lupus erythematosus (SLE), multiple sclerosis, acute infectious diseases, asthma, atopic dermatitis, and psoriasis. Besides TNF-α, ADAM17 also regulates a macrophage colony stimulating factor or chemokine, fractalkine (FKN). As a result, ADAM17 inhibitors are viewed as potential candidates for treating inflammation-related diseases. Unfortunately, previous studies have shown that broad-spectrum ADAM inhibitors possess tissue toxicity. Thus, there remains a challenge to develop highly selective small molecule inhibitors of the conserved ADAMs family.
In 1998, Craig Mello and Andrew Farr discovered gene silencing. Thereafter Tuschl and his colleagues found that chemically synthesized siRNAs of 19 to 25 bp can specifically and efficiently silence target mRNAs in mammalian cells. Since then, siRNA has been widely used for gene function study and disease treatment.